Researchers have identified a new bodily defense mechanism deployed in the fight against urinary tract infections (UTIs). UTIs are very common and affect more women than men. The leading cause of UTIs is exposure to uropathogenic E. coli bacteria, also referred to as UPEC. While antibiotics resolve many infections, recurrence is common, and antibiotic resistance is rising; a better understanding of the natural course of UTIs could help lead to new treatments. In addition to flushing bacteria and infected bladder cells out of the urinary tract through urination, the body employs innate defenses, such as production of antimicrobial molecules, to stymie UTIs. In a new study, scientists investigated a suspected defense molecule called lipocalin 2 (LCN2). It is known that LCN2 can arrest the growth of E. coli and certain other bacteria by limiting their access to the essential nutrient iron. The researchers found that levels of LCN2 were very high in the urine of patients suffering from UTIs and fell as the UTIs resolved. Through experiments in female mice, they confirmed that urine levels of LCN2 rose in response to infection with UPEC, and that mice lacking LCN2 cleared UTIs much more slowly. By tagging both mouse cells and UPEC with light-emitting molecules and other visually detectable markers, the researchers were able to track the primary source of LCN2 during an infection to cells in the kidney called alpha-intercalated cells. Mice lacking these kidney cells were less well able to suppress UTIs. These specialized kidney cells help maintain the acid pH of urine; when mice were exposed to UPEC, these cells quickly acidified their urine even further, which appears to be yet another defense against bacterial infection. While the exact mechanism has yet to be determined, evidence from this study suggests that contact with molecules produced by UPEC and/or with the bacteria themselves stimulates these kidney cells both to produce the LCN2 defense molecule and to acidify the urine within hours of infection. Discovery of this acute response that effectively targets the most common cause of UTIs expands the role played by the kidney in innate defense against such infections, and could also provide new insight into why diseases that damage the kidney’s alpha-intercalated cells leave patients more susceptible to UTIs.